There are few reports of successful transmission of Leishmania to experimental animals by bite, and none have explored the host inflammatory and immune response to sand fly-initiated infections. A reproducible murine ear model of L. major-transmission by bite of its natural vector Phlebotomus papatasi has been established and extensively studied. The model explores changes in immune response and in disease outcome following several exposures of the mice to the bites of uninfected sand flies. The results clearly indicate that preexposure to the bite of uninfected sand flies protects both BALB/c and C57Bl/6 mice against Leishmania infection, corroborating prior studies using needle inoculation of salivary gland lysate and needle challenge. The mice preexposed to sand fly bites displayed a DTH response in the dermis that was associated with a clear-up regulation of INF-gamma- producing epidermal cells following transmission by bite. The early induction of IFN gamma in the skin in response to salivary antigens may underlie the protection observed as a result of pre-exposure to sand fly saliva. Leishmania promastigotes synthesize an abundance of phosphoglycans which are either present on the cell surface anchored by PI (lipophosphoglycan, LPG) or secreted as protein-containing glycoconjugates. These phosphoglycan-containing molecules have been implicated in promoting the survival of the parasite within both its vertebrate and invertebrate hosts. The role of the phosphoglycan- containing glycoconjugates in Leishmania/sand fly interactions was explored using mutant promastigotes specifically deficient or rescued for expression of genes involved in distinct steps in LPG biosynthesis. The mutants have revealed dual roles for phosphoglycans as virulence molecules in the sand fly vector: 1) Whereas LPG is not essential for parasite survival in the early blood-fed midgut, secreted phosphoglycan-containing proteins are required to protect promastigotes from the digestive enzymes in the gut, and 2) LPG is required to mediate midgut attachment and to maintain infection in the fly during excretion of the digested bloodmeal. - Cutaneous leishmaniasis, sand flies, lipophosphoglycan, skin, saliva, interferon gamma, IL-4